Viral carcinogenesis: factors inducing DNA damage and virus integration

Abstract

Viruses are the causative agents of 10%-15% of human cancers worldwide. The most common outcome for virus-induced reprogramming is genomic instability, including accumulation of mutations, aberrations and DNA damage. Although each virus has its own specific mechanism for promoting carcinogenesis, the majority of DNA oncogenic viruses encode oncogenes that transform infected cells, frequently by targeting p53 and pRB. In addition, integration of viral DNA into the human genome can also play an important role in promoting tumor development for several viruses, including HBV and HPV. Because viral integration requires the breakage of both the viral and the host DNA, the integration rate is believed to be linked to the levels of DNA damage. DNA damage can be caused by both endogenous and exogenous factors, including inflammation induced by either the virus itself or by co-infections with other agents, environmental agents and other factors. Typically, cancer develops years to decades following the initial infection. A better understanding of virus-mediated carcinogenesis, the networking of pathways involved in transformation and the relevant risk factors, particularly in those cases where tumorigenesis proceeds by way of virus integration, will help to suggest prophylactic and therapeutic strategies to reduce the risk of virus-mediated cancer.

Figure 1

Integration of HBV, HPV and MCV viral DNAs into the human genome induces cellular and viral responses and further contributes to carcinogenesis (HBV, hepatitis B virus; HPV, high-risk human papillomaviruses; MCV, Merkel cell polyomavirus; MCC, Merkel cell carcinoma; TERT, telomerase reverse transcriptase; MLL4, Mixed-lineage leukemia 4).